GLUCOSE CATABOLISM IN CANCER-CELLS - THE TYPE-II HEXOKINASE PROMOTER CONTAINS FUNCTIONALLY ACTIVE RESPONSE ELEMENTS FOR THE TUMOR-SUPPRESSOR P53

The p53 tumor suppressor is found to be mutated and abundant in a wide variety of tumors. Within tumors showing rapid growth, the Type II is oform of hexokinase is also highly expressed to facilitate high rates of glucose catabolism, which in turn promote their rapid proliferation . We previously reported isolation of the proximal promoter of the Typ e II hexokinase gene from the highly glycolytic hepatoma AS-30D (Mathu pala, S. P., Rempel, A., and Pedersen, P. L. (1995) J. Biol. Chem. 270 , 16918-16925). Here, we show that a p53 protein, exhibiting two point mutations in its cDNA, is abundantly expressed in the AS-30D hepatoma . Co-expression studies showed that p53 overexpression significantly a nd reproducibly activated the Type II hexokinase promoter. Two functio nal p53 motifs were identified within this promoter by footprint and g el retardation analyses. Presence of functional p53 response elements on the Type II hexokinase promoter and the positive regulatory effect on the promoter by the mutant p53 indicates that in rapidly growing li ver tumors, and perhaps in many other tumors as well, this highly abun dant p53 protein plays a role in maintaining a high glycolytic rate. T his is the first report of a possible link between less of cell cycle control in rapidly growing cancer cells and their high glycolytic phen otype.